Hypertension is a widespread circulatory disease which afflicts millions of warm-blooded animals. It is manifested by high blood pressure and is accompanied by a loss of elasticity (compliance) of the arteries. The causes of some hypertensive conditions are not known, i.e., in cases of essential hypertension. Other types of high blood pressure are caused by specific diseases, e.g., primary aldosteronism, aortic coarctation, renal stenosis, and pheochromocytoma.
To date, many chemotherapeutic agents are used to treat hypertension. Their effects are maintained by either venous expansion, i.e., reducing venous return to the heart and causing a lowering of arterial blood pressure, or by static arterial vasodilation. None of the agents presently in use treat the disease per se, they only treat the symptoms, which symptoms return quickly upon cessation of treatment.
There is thus a need for an agent which reduces arterial blood pressure and meets the following criteria:
(a) increases compliance of the blood vessels PA0 (b) has essentially no effect on the heart rate PA0 (c) is orally absorbed PA0 (d) is effective in small doses with infrequent administration PA0 (e) has a good therapeutic index PA0 (f) has no significant diuretic action PA0 (g) treats the disease rather than the symptoms only PA0 (h) causes no manifestations of cardiovascular compensation PA0 (i) is not effective by action on the nervous system PA0 (j) does not cause a venous pooling, and PA0 (k) can be combined with known antihypertensive agents.
According to this invention it has been discovered that pharmaceutical compositions containing an effective antihypertensive amount of, as the active agent, a compound characterized by being a naturally occurring polyether ionophore, or derivatives of such compounds, will fulfill the criteria set forth above.
Polyether ionophores are compounds which facilitate the transport of monovalent or divalent cations across a membrane. The "polyether" nature of the ionophore refers to the considerable number of tetrahydro-pyrans and -furans found in the ionophore structure. For the most part, these compounds have been found to exhibit weak antibiotic activity. Other utilities for many of these compounds include activities as growth promotants (U.S. Pat. No. 3,839,557), coccidiostatic agents (U.S. Pat. Nos. 3,719,753 and 3,577,531) and cardiovascular agents (U.S. Pat. No. 3,873,715).
Pressman et al., discoverers of the therapeutic effect of certain of the polyether ionophores as cardiovascular agents, determined that significant changes in myocardial force of contraction, heart rate and blood pressure could be achieved following intravenous injection of certain polyether ionophores. Pressman et al. found that cardiac output, blood pressure, stroke volume and contractile force were all substantially increased by intravenous administration of selected polyether ionophores. It was therefore unexpected and surprising to find that chronic oral administration of polyether ionophores at low dosage levels, when compared to cardiotonic active amounts, produced a significant decrease in arterial blood pressure in warm-blooded hypertensive animals with concomitant changes in the hemodynamic profile toward the normal state.
With or without a lowering of arterial blood pressure, cardiovascular diseases, such as angina, claudication and decreased blood flow to the brain would be expected to be positively affected, by chronic administration at low dosage levels of the disclosed polyether ionophores. This is due to the fact that arterial blood flow is enhanced by decreasing pulse wave velocity secondary to increasing compliance so that blood flow is now regulated by a normal physiologic mechanism, i.e., a pressure gradient (potential energy) rather than kinetic energy.
Thus, another utility of the present compounds would be in the treatment of warm-blooded animals which are not hypertensive but who manifest cardiovascular diseases such as discussed above.
The following compilation represents typical polyether compounds which exhibit an ionophoric effect and are useful in treating hypertension and in reverting the hemodynamic profile to a normal state. The formulas which follow utilize the shorthand notations Me and Et which represent methyl and ethyl, respectively.